Abstract
The underlying mechanism of necroptosis in relation to cancer is still unclear. Here, MYC, a potent oncogene, is an antinecroptotic factor that directly suppresses the formation of the RIPK1–RIPK3 complex. Gene set enrichment analyses reveal that the MYC pathway is the most prominently down-regulated signaling pathway during necroptosis. Depletion or deletion of MYC promotes the RIPK1–RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. Interestingly, MYC binds to RIPK3 in the cytoplasm and inhibits the interaction between RIPK1 and RIPK3 in vitro. Furthermore, MYC-nick, a truncated form that is mainly localized in the cytoplasm, prevented TNF-induced necroptosis. Finally, down-regulation of MYC enhances necroptosis in leukemia cells and suppresses tumor growth in a xenograft model upon treatment with birinapant and emricasan. MYC-mediated suppression of necroptosis is a mechanism of necroptosis resistance in cancer, and approaches targeting MYC to induce necroptosis represent an attractive therapeutic strategy for cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 19982-19993 |
| Number of pages | 12 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 117 |
| Issue number | 33 |
| DOIs | |
| Publication status | Published - 2020 Aug |
Bibliographical note
Funding Information:program (both to J. Song); a grant from the Basic Science Research Program through the NRF funded by the Ministry of Education (NRF-2019R1C1C1002831); a grant from the Korea Research Institute of Bioscience and Biotechnology Research Initiative Program (to E.-W.L.); a grant from Graduate School of Yonsei University Research Scholarship Grants in 2020 (to D.S.); and grants from the
Funding Information:
National Cancer Center (1710080) and the NRF (NRF-2017M3A9F9030648) (both to D.H.S). Research in the P.V. group is supported by Flemish grants (EOS MODEL-IDI consortium, G.0C31.14N, G.0C37.14N, G.0E04.16N, G.0C76.18N, and G.0B71.18N), Methusalem (BOF16/MET_V/007), ‘Foundation against Cancer’ (FAF-F/2016/865), and the Vlaams Instituut voor Biotechnologie.
Funding Information:
ACKNOWLEDGMENTS. This study was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A3A2066581) and Brain Korea 21 (BK21) PLUS
Funding Information:
This study was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A3A2066581) and Brain Korea 21 (BK21) PLUS program (both to J. Song); a grant from the Basic Science Research Program through the NRF funded by the Ministry of Education (NRF-2019R1C1C1002831); a grant from the Korea Research Institute of Bioscience and Biotechnology Research Initiative Program (to E.-W.L.); a grant from Graduate School of Yonsei University Research Scholarship Grants in 2020 (to D.S.); and grants from the National Cancer Center (1710080) and the NRF (NRF-2017M3A9F9030648) (both to D.H.S). Research in the P.V. group is supported by Flemish grants (EOS MODEL-IDI consortium, G.0C31.14N, G.0C37.14N, G.0E04.16N, G.0C76.18N, and G.0B71.18N), Methusalem (BOF16/MET_V/007), ‘Foundation against Cancer’ (FAF-F/2016/865), and the Vlaams Instituut voor Biotechnologie.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
All Science Journal Classification (ASJC) codes
- General
